AKT inhibitors in research and application

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Published: 25 Apr 2018
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Dr Brian Schwartz - ArQule, Burlington, USA

Dr Brian Schwartz talks to ecancer at AACR 2018 about the latest developments from ArQule.

He specifically discusses the improvement of their AKT inhibitors after the last few years and future prospects.

We have been developing AKT inhibitors now for the last ten years. Our first generation AKT inhibitor is a really unique molecule, it’s primarily allosteric which targets AKT1, 2 and 3. It works in a unique way in that it inhibits both the active and the inactive form of AKT in cells, so a little bit different from the either purely allosteric molecule, MKT206, or the ATP competitive molecules from Genentech which have been presented here at this meeting. So a unique molecule, very nice preclinical package. We entered into the clinic a number of years ago and actually presented our first in-human here at AACR I think about four years ago where we showed nice target engagement. But the problem with the molecule as we went through the phase I is the therapeutic index was narrow. When we started to get efficacy in a specific molecular subset, that of either AKT mutant cancers or PI3K activating or hotspot mutations, we also got significant toxicities. We tried with schedule changes to see if we could get away from the toxicity so we instituted breaks. Unfortunately at the end of the programme we were really unable to come up with a nice single agent regimen that could be administered on a continuous basis.

We were really lucky at the time in that we were approached by David Hyman at Memorial Sloan Kettering who was very familiar with the concept of combining AKT inhibitors with aromatase inhibitors or other hormonal therapy in either endometrial or ovarian cancer. He had also done a lot of work in breast cancer. So he postulated that we’d be able to give our inhibitor for shorter periods of time, a longer break, that of five days on with a nine day break, in combination with aromatase inhibitor and our agent could potentially be used at slightly lower doses than was used in the phase I trials.
So we started a cohort of patients with both PI3K/AKT mutant disease plus ER positive in patients who could potentially benefit from an aromatase inhibitor. We looked for both targets, two different drugs, a well-known entity in endometrial or ovarian cancer. The first few patients we treated at the higher dose of AKT and we saw the standard AKT related toxicities, primarily hypoglycaemia, rash or he had a couple of patients with AST or ALT elevation. We dropped the dose to 150 and the safety really cleared up. We did quite a bit of PK as well and we were able to show that we were clearly in the therapeutic range that we wanted to be with our AKT inhibitor.

Then, lastly, the efficacy component. Almost all the patients who were started at 200 had to dose escalate within one or two cycles down to 150. Even at that schedule he produced one CR and then a number of best responses of partial responses. Some did not confirm but a really nice signal for that type of patient population. What was also interesting, he had full genomic sequencing on all these patients. So we have a feel now for which PI3K mutations respond to the drug so, for example, the common 1047 mutations and some of the uncommon mutations the patients progressed really quickly. So as we expand the study, get more information, we’ll be able to select a population that would benefit even more greatly from this combination.

What we also did is we went back and looked at all our endometrial cancer patients treated with this agent as a single agent. One of the problems is that they were treated from 20mg all the way up to 700mg so a huge dose spectrum and what was clear from that is that the patients with PI3K or AKT mutations also benefitted, not to the same degree as the combination, but also benefit more than the patients without the mutations. So a really nice subset.

Next steps for the trial are really to expand the cohort, put on another 10-15 patients. We’ve got a nice signal in serous. So endometrial cancer is divided up by both histology, mutational status and then hormonal status, these three different buckets. It looks like the serous histology and the activating PI3K/AKT mutations may be the area we want to focus on, the expansion cohort. Once we’ve completed that piece the next step will really be to decide what are the next steps for the drug. Endometrial cancer right now is a really high unmet medical need; mTOR inhibitors in combination with aromatase inhibitors, and mTOR inhibitors are downstream, have shown some degree of efficacy. So we know that the pathway is important, it’s a matter of selecting the right group of patients on this therapy -  low dose AKT, normal dose aromatase inhibitor – and put that into some kind of randomised or enriched study, hopefully for the next stage of development, phase II, phase III, dependent on how the data goes.

So that’s the 092 oncology piece that we’d really like to explore. We’re quite encouraged from this meeting from the data that has been presented by some other companies with their AKT inhibitors, for example Genentech’s agent in combination, which shows that also in enriched populations you see benefit with these agents in combination either with chemo or other hormonal therapies in hormone sensitive tumours.

What’s to come in the future?

The other thing that we strived… we were a research development, now we’re primarily a development company. We always strived to try and make our molecules better. So while we had started miransertib in the clinic, we also kept on trying to improve it. We knew the weaknesses of that molecule were it accumulated, it maybe wasn’t as potent, it’s a very selective compound, but the therapeutic index in our animal toxicity studies was relatively narrow. So we kept on modifying that agent and came up with a nice second generation that had a much wider therapeutic index in the same animal studies, much better pharmaceutical properties and not much accumulation.

So we’ve gone into the clinic. The first two cohorts, we’ve learned from our mistakes, we went straight with MD Anderson and we presented this poster yesterday, straight into an enriched population - AKT mutant, PI3K mutant and PTEN. We also allowed some patients with amplification, but an enriched group to start with. The first two cohorts we didn’t see much; once we got to reasonable exposures we observed a partial response which still needs to be confirmed and five out of the additional nine patients treated all had stable disease or better or marked changes. So really encouraging signals if our therapeutic index is bigger, so let’s say 25. We haven’t hit our DLTs, let’s say our DLT is 100, 150, it makes it a much easier jump, and we have a lot of experience around AKT so it will be easy to move it into the next phase quite quickly.